E3 Ubiquitin Ligase VHL Regulates Hypoxia-Inducible Factor-1α to Maintain Regulatory T Cell Stability and Suppressive Capacity.

Abstract

Foxp3(+) regulatory T (Treg) cells play a critical role in immune homeostasis; however, the mechanisms to maintain their function remain unclear. Here, we report that the E3 ubiquitin ligase VHL is essential for Treg cell function. Mice with Foxp3-restricted VHL deletion displayed massive inflammation associated with excessive Treg cell interferon-γ (IFN-γ) production. VHL-deficient Treg cells failed to prevent colitis induction, but converted into Th1-like effector T cells. VHL intrinsically orchestrated such conversion under both steady and inflammatory conditions followed by Foxp3 downregulation, which was reversed by IFN-γ deficiency. Augmented hypoxia-inducible factor 1α (HIF-1α)-induced glycolytic reprogramming was required for IFN-γ production. Furthermore, HIF-1α bound directly to the Ifng promoter. HIF-1α knockdown or knockout could reverse the increased IFN-γ by VHL-deficient Treg cells and restore their suppressive function in vivo. These findings indicate that regulation of HIF-1α pathway by VHL is crucial to maintain the stability and suppressive function of Foxp3(+) T cells.

• Authors: Jee H Lee, Chris Elly, Yoon Park, Yun-Cai Liu
• Journal: Immunity (Immunity) Vol. 42 Issue 6 Pg. 1062-74 (Jun 16 2015) ISSN: 1097-4180 [Electronic] United States
• PMID: 26084024 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Small Interfering
• Interferon-gamma
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, mouse

Topics

• Animals
• Cells, Cultured
• Cellular Reprogramming (genetics)
• Colitis (immunology)
• Down-Regulation (genetics)
• Forkhead Transcription Factors (genetics, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Immune Tolerance
• Inflammation (genetics)
• Interferon-gamma (genetics, metabolism)
• Lymphocyte Activation (genetics)
• Mice
• Mice, Inbred Strains
• Mice, Knockout
• Mice, Transgenic
• RNA, Small Interfering (genetics)
• T-Lymphocytes, Regulatory (immunology)
• Th1 Cells (immunology)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics, metabolism)